Vanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. A wide variety of Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285. Particularly notable examples of vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or —N-(4-hydroxy-3-methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).
Vanilloid Receptor (VR-1) has now been renamed as TRPV1 (Transient Receptor Potential Vanilloid subfamily member 1). TRPV1 is a calcium-permeable, ligand gated ion channel which is highly expressed in sensory neurones (Caterina M J, Schumacher M A, Tominaga M, Rosen T A, Levine J D and Julius D (1997) Nature 389, 816-824) whose function is modulated by such Vanilloid compounds. TRPV1 has been studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51, No. 2.). TRPV1 plays a key role in peripheral neuronal signalling where it mediates depolarising, excitatory responses to noxious stimuli such as heat, add and capsaicin, the pungent component in chilli peppers (Szallasi et al, Nature Reviews Drug Discovery, 6, 357-372 (2007). TRPV1 acts as a polymodal receptor, responding in an integrative manner to an extensive array of activators including products of inflammation such as histamine, prostaglandins and bradykinin (which activate indirectly via protein kinase A and protein kinase C) as well as eicosanoid derivatives such as HPETEs, anandamide and environmental irritants. Upon activation, the channel pore opens and allows influx of cations which depolarises the nerve membrane and triggers neuronal axonal firing and/or local release of neurotransmitters such as Substance P and CGRP. Activation may be caused by a single trigger, such as pH, but may be caused by integration of different triggers acting in concert on the channel.
The role of TRPV1 in disease has been studied extensively in pain models where a role in both thermal and post-inflammatory hyperalgesia is well established (Chizh et al, Jara-Oseguera et al, 2008). TRPV1 has also been implicated in other diseases where symptoms are potentially driven wholly or in part by neuronal hypersensitivity or hyperactivity, because of its role in sensory signalling in peripheral nerves. Such diseases include asthma, rhinitis, cough, overactive bladder, reflux oesophagitis, irritable bowel syndrome and migraine. TRPV1 has been implicated to have a role in the afferent sensory loop of the cough reflex and the heightened cough sensitivity seen in disease (Grace, Dubuis, Birrell, Belvisi (2012), TRP Channel Antagonists as Potential Antitussives, Lung 190: 11-15, and Gu and Lee (2011), Airway irritation and cough evoked by acid: from human to ion channel, Current Opinion in Pharmacology 11: 238-247). TRPV1 has been implicated in inflammatory responses occurring in dry eye syndrome (Pan, Wang, Yang, Zhang & Reinach (2010), TRPV1 Activation is Required for Hypertonicity Stimulated Inflammatory Cytokine Release in Human Corneal Epithelial Cells, Manuscript IOVS, 10-5801). TRPV1 is also implicated to play a role in metabolic diseases such as diabetes and obesity (Motter A L & Ahern G P (2008) FEBS Letters 582, 2257-2262; Suri & Szallasi A (2007), The emerging role of TRPV1 in diabetes and obesity, Trends in Pharm Sci, Rasavi et al (2006) Cell 127, 1123-1135.)
TRPV1 expression is not limited only to peripheral sensory nerves, but is also expressed in spinal cord and in various regions of the central nervous system. TRPV1 is also found in non-neuronal cells and tissues including various types of epithelial cell and immune cells such as mast cells and dendritic cells (Khairatkar-Joshi N & Szallasi A (2008) Trends in Molecular Medicine. 
International Patent Applications, Publication Numbers WO 02/08221, WO 02/16317, WO 02/16318 and WO 02/16319 each disclose certain TRPV1 antagonists and their use in the treatment of diseases associated with the activity of TRPV1.
Patent application Number WO 03/022809 discloses urea derivatives including N-(2-Bromophenyl)-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea and N-(3-methyl-5-isoquinolinyl))-N′-[(3R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea or pharmaceutically acceptable salts thereof and their use in the treatment of diseases associated with the activity of TRPV1.
Patent application Number WO 10/026,129 discloses N-(2-Bromophenyl)-N′-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea for use in the treatment of rhinitis. Patent application Number WO 10/026,128 discloses N-(3-methyl-5-isoquinolinyl))-N′-[(3R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea for use in the treatment of rhinitis.
It is an object of the invention to provide further TRPV1 antagonists.